Regulated intracellular proteolysis occurs through the ubiquitin-proteasome pathway, and proteasome inhibitors (PIs) have been validated as key therapeutic agents in multiple myeloma by studies from our group and others. Plasma cell capacity for protein turnover is reduced during their development, while they are at the same time faced with a high load of misfolded immunoglobulins, creating an imbalance and cellular stress which are further exacerbated by PIs, which may explain their unique sensitivity to this class of drugs. However, only a minority of patients in the relapsed/refractory setting achieve complete remissions with single agent therapy, while the vast majority eventually develop drug resistance. Our group has made the novel observation that chaperones responsible for new proteasome assembly, and their associated signaling pathways, are activated in the setting of PI resistance. Moreover, interruption of these pathways can both sensitize to PIs in the drug-nave setting, and overcome PI resistance in vitro and in vivo. These findings support our central hypothesis, which proposes that primary and secondary PI resistance is mediated by proteasome assembly chaperones which promote cellular expansion of proteasome capacity, and that these chaperones and their associated pathways are rational biomarkers of PI sensitivity, as well as potential targets for approaches to enhance the efficacy of PIs. To evaluate these possibilities, additional studies are proposed to further dissect the molecular pathways involved in proteasome assembly and PI resistance. In addition, genomic studies will be performed in association with prospective cooperative group trials of bortezomib and carfilzomib to validate the possibility that expression of one of our genes of interest, MUC20, and associated activation signatures of HGF/c-MET and p44/42 MAPK, may help to identify patients who are most likely to benefit from PI-based therapy. Finally, approaches to suppress the activity of these pathways, or possibly of enhancing MUC20 expression, will be evaluated for their ability to induce chemosensitization, and overcome chemoresistance in cell lines, primary samples, and physiologically relevant in vivo murine models.